Pivotal role of signal transducer and activator of transcription (Stat)4 and Stat6 in the innate immune response during sepsis

Signal transducer and activator of transcription (Stat)4 and Stat6 are tran scription factors that provide type 1 and type 2 response, respectively. He re, we explored the role of Stat4 and Stat6 in innate immunity during septi c peritonitis. Stat4(-/-) and Stat6(-/-) mice were resistant to the lethali ty compared with wild-type (WT) mice. At the mechanistic level, bacterial l evels in Stat6(-/-) mice were much lower than in WT mice, which was associa ted with increased peritoneal levels of interleukin (IL)-12, tumor necrosis factor (TNF)-alpha, macrophage-derived chemokine (MDC), and C10, known to enhance bacterial clearance, In Stat4-/- mice, hepatic inflammation and inj ury during sepsis were significantly ameliorated without affecting local re sponses. This event was associated with increased hepatic levels of IL-10 a nd IL-13, while decreasing those of macrophage inflammatory protein (MIP)-2 and KC. Sepsis-induced renal injury was also abrogated in Stat4(-/-) mice, which was accompanied by decreased renal levels of MIP-2 and KC without al tering IL-10 and IL-13 levels. Thus, Stat6(-/-) and Stat(4-/-) mice appeare d to be resistant to septic peritonitis by enhancing local bacterial cleara nce and modulating systemic organ damage, respectively, via balancing cytok ine responses. These results clearly highlight an important role of local t ype 1 and systemic type 2 cytokine response ill protective immunity during sepsis, which can be regulated by Stat proteins.